This research proposes to develop new knowledge relevant to the treatment of cancer by conducting Phase I studies of new anticancer drugs and pharmacologic modulatory regimens which attempt to enhance the therapeutic efficacy of new drugs. Concurrent with the clinical studies, the research will evaluate the distribution and metabolism of the study drugs and examine their biological effects at the clinical biochemical and molecular level. Three separate focus areas are planned to capitalize on the expertise of the MSKCC scientific community. These areas are: 1. Putative Cytodifferentiation Agents: The institution has a long-standing interest in differentiation agents including studies of HMBA, all trans-retinoic acid, 9-cis retinoic acid, RXR specific ligands and most recently Phenylbutyrate. 2. Signal Transduction Targets: MSKCC laboratories have national leadership roles in the evaluation of ras inhibitors, ceramide mediated signaling, antibodies against growth factor receptors and the interaction between growth factors and cytotoxic chemotherapy. Trials of these agents, alone and in combination with cisplatin are planned. 3. Antifols and related anti Metabolites: Several new antimetabolites have entered clinical trials and the combination of these new anti metabolites with established drugs are planned for the initial grant period. The studies to be performed during the funding period will include pharmacokinetic studies, studies of adaptive dosing and pharmacodynamic studies of new agents or combinations. Laboratory correlates, based on tumor biopsies or surrogate tissues will also be performed.